Organoids From Mucinous Appendiceal Adenocarcinomas as High-Fidelity Models for Individual Therapy

Guangyao Liu; Xing Xiao; Yujian Xia; Weibing Huang; Wei Chen; Jiannan Xu; Songyao Chen; Huijin Wang; Jitao Wei; Huan Li; Man Shu; Xiaofang Lu; Changhua Zhang; Yulong He

doi:10.3389/fmed.2022.829033

Organoids From Mucinous Appendiceal Adenocarcinomas as High-Fidelity Models for Individual Therapy

Front Med (Lausanne). 2022 Jun 2:9:829033. doi: 10.3389/fmed.2022.829033. eCollection 2022.

Authors

Guangyao Liu¹, Xing Xiao¹, Yujian Xia², Weibing Huang¹, Wei Chen¹, Jiannan Xu¹, Songyao Chen¹, Huijin Wang¹, Jitao Wei¹, Huan Li¹, Man Shu³, Xiaofang Lu⁴, Changhua Zhang¹, Yulong He^{1

5}

Affiliations

¹ Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
² Department of Gastrointestinal Surgery, Northern Jiangsu People's Hospital, Yangzhou, China.
³ Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
⁴ Department of Pathology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
⁵ Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Abstract

Background: Mucinous appendiceal adenocarcinoma (MAA) is a rare, heterogeneous disease. Patients with unrespectable mucinous appendiceal adenocarcinoma presenting with peritoneal spread are treated by intraperitoneal chemotherapy, hyperthermic intraperitoneal chemotherapy, systemic chemotherapy, or targeted therapy. However, there are no guidelines for efficacious drugs against mucinous appendiceal adenocarcinoma. Therefore, relevant high-fidelity models should be investigated to identify effective drugs for individual therapy.

Methods: Surgical tumor specimens were obtained from a mucinous appendiceal adenocarcinoma patient. The tissue was digested and organoid culture was established. H&E and immunohistochemistry staining as well as DNA sequencing was performed on tissue and organoid. The pathological characteristics and gene mutations of the organoid were compared to those of the original tumor. Drug sensitivity tests were performed on organoid and the patient clinical responds to chemotherapy and targeted therapy was compared.

Results: Organoids were successfully established and stably passaged. Pathological characteristics of organoids including H&E staining and expression of protein markers (CK20, CDX-2, STAB2, CD7, PAX8) were consistent to those of the original tumor. Moreover, the organoids carried the same gene mutations as the primary tumor. Sensitivity of the organoids to chemotherapeutic drugs and tyrosine kinase inhibitors included: 5-FU (IC₅₀ 43.95 μM), Oxaliplatin (IC₅₀ 23.49 μM), SN38 (IC₅₀ 1.02 μM), Apatinib (IC₅₀ 0.10 μM), Dasatinib (IC₅₀ 2.27 μM), Docetaxel (IC₅₀ 5.26 μM), Regorafenib (IC₅₀ 18.90 μM), and Everolimus (IC₅₀ 9.20 μM). The sensitivities of organoid to these drugs were comparable to those of the patient's clinical responses.

Conclusion: The mucinous appendiceal adenocarcinoma organoid model which retained the characteristics of the primary tumor was successfully established. Combined organoid-based drug screening and high throughput sequencing provided a promising way for mucinous appendiceal adenocarcinoma treatment.

Keywords: chemotherapy; drug sensitivity test; individualized therapy; mucinous appendiceal adenocarcinoma; organoid culture.